BRIEFING PAPER

Managing infectious
disease outbreaks
through rapid pathogen
genome sequencing
February 2021

nanoporetech.com
1
Introduction
With over two million attributed deaths to
date and a projected economic cost of
$28 trillion1, the COVID-19 pandemic has
refocused global attention on the acute,
ever-present threat of infectious disease.
Executive summary
• The threat of infectious disease is ever present —
caused by seasonal and novel viruses, bacteria,
and fungi — and further compounded by growing
antimicrobial resistance
• Significant outbreaks are an increasing risk, driven
by globalisation, population growth, urbanisation,
and climate change
• Preparedness is key to minimising the potentially
devastating impacts of these outbreaks
• Genomic epidemiology, powered by rapid, accessible
sequencing technology, provides vital information
and time savings essential for rapid disease identification
and control
• Investment in national and regional disease surveillance
and monitoring infrastructure is critical
2 OXFORD NANOPORE TECHNOLOGIES | SEQUENCING, GENOMIC EPIDEMIOLOGY, AND INFECTIOUS DISEASE
Global health security depends on the rapid
recognition and containment of infectious diseases
and no government can afford to be complacent
about the risks posed to population health,
economic, political, and social stability and
wellbeing. It is possible to be prepared to prevent
and control such threats by investing in intelligent
and agile public health tools to monitor for potential
risks, enabling responses at appropriate speed and
scale to problems as they appear.
Genomic epidemiology is a crucial weapon in the
public health fight against infectious diseases,
providing rapid identification and complete
characterisation of infectious disease pathogens.
As evidenced by the COVID-19 pandemic, genomic
epidemiology further supports precise tracking of
pathogen evolution, providing detailed insights into
sources of infection, routes of transmission, and the
potential association of novel pathogen variants
(such as the COVID-19 B1.1.7 and B1.351 variants
originally identified in the UK and South Africa) with
changes to disease severity, transmission, and
diagnostic and therapeutic efficacy.
This briefing paper describes when, where, and how
genomic epidemiology can offer critical and timely
insights for infectious disease experts, public health
professionals, and policy-makers to stay a step
ahead of infectious disease threats, responding with
maximal effect.
This briefing paper is published by Oxford
Nanopore Technologies. Our low-cost, scalable
genomic sequencing devices have been used
extensively to rapidly characterise pathogens and
track outbreaks, enabling informed and decisive
action. See page 32 for more information.
“ [COVID-19 is a] wake-up
call and a dress rehearsal
for future challenges.
António Guterres, Secretary-General, United Nations2
“

3
The importance of managing infectious disease threats
KEY MESSAGES
• Infectious diseases are an increasing threat
• Outbreaks can have devastating health and
economic consequences
Even a relatively small and well-controlled
outbreak can exacerbate existing pressures
on healthcare systems, whilst major
outbreaks may overwhelm them. Serious
epidemics also pose significant risks of
wider social and economic destabilisation.
Estimated economic impacts of recent infectious disease outbreaks.
Data from WHO3. (US dollars)
SARS (2003) H1N1 (2009)
40
billion
40-50
billion
4 OXFORD NANOPORE TECHNOLOGIES | SEQUENCING, GENOMIC EPIDEMIOLOGY, AND INFECTIOUS DISEASE
After an epidemic has subsided, there may be
longer-term local, national, and global adverse
effects on employment, health, education, trade,
travel, and quality of life. According to the
International Monetary Fund (IMF), the economic
impact of the current COVID-19 pandemic could
be in the region of US $28 trillion1.
Significant new outbreaks are an ongoing risk,
driven by increasing globalisation, population
growth, urbanisation, and climate change. They may
arise from the resurgence of historical infectious
diseases and the spread of antibiotic resistance,
or the emergence of infectious diseases caused by
novel infectious agents (Figure 1). Novel pathogens
are particularly dangerous, because of the time
needed to understand the disease, and to develop
control measures and treatments. Dr Michael Ryan,
Executive Director of the World Health Organization
(WHO) Emergencies Programme, recently
described constant outbreaks of serious infectious
diseases as ‘a new normal’ for which countries need
to be ready4.
Ebola (2014-16) COVID-19 (2019-)
28
53
billion
Although diseases passed between humans are the
most urgent concern, infectious agents that cause
disease in wild or domestic animals and plants can
also have severe economic and environmental
impacts, and indirectly or directly harm human
health; for example, foodborne disease is a major
burden in low and middle-income countries5.
Preparedness is vital to minimise the damage
infectious diseases can cause. Even small delays
or mistakes in response can have significant
implications for public health, and modest changes
in outcome have much wider effects. For example,
it has been suggested that the 2003 severe acute
respiratory syndrome (SARS) outbreak would have
tripled in size had there been a delay of just one
week in applying control measures6.
Examination of the relative success of New Zealand
in control of the COVID-19 pandemic highlighted
that the key elements were early, decisive reactions
from health authorities, effective surveillance
(including genomic surveillance systems), and
targeted testing strategies7.
trillion
2009 2019
H1N1 2012 COVID-19
influenza A new disease
(swine flu)
MERS
2014 new disease

EBOLA
2003
2015 SARS 2005
new disease

Zika H5N1
Avian flu

Figure 1: Selected infectious disease outbreaks in the 21st century

Infectious diseases are an increasing threat, for example in 2019 alone the
WHO recorded over 100 outbreaks of 19 different infectious diseases, each
posing a potential epidemic or pandemic threat3.

5
Understanding infectious diseases
KEY MESSAGES
• Effective treatments are not available for all
pathogens and drug resistance is increasing
• Prevention of transmission is critical to
managing infectious disease
• Pathogen genome sequencing is a key
technique for identifying and understanding
infectious organisms
Infectious diseases are caused by
pathogenic microorganisms (microbes),
including viruses, bacteria, fungi, and
parasites. They can cause disease of
varying type and severity, and many
are easily spread through close contact
between people. New human pathogens
often come from microbes that normally
infect animals, but have also acquired
the ability to infect humans.
A wide range of anti-microbial drugs are currently
available, though in recent years the spread of
antimicrobial resistance, especially in bacteria, has
reduced the effectiveness of some treatments.
Detecting antimicrobial resistance in patients with
bacterial infections is critical to ensuring that
effective alternative treatments can be used8 or for
the identification of particularly dangerous cases
where no current antibiotics will work, such as
carbapenem-resistant infections9. Vaccination to
prevent infection is possible for certain diseases,
though even then some microbes such as influenza
virus change so quickly that new vaccinations are
needed every year; for many disease threats, no
vaccines exist.
Given these limitations, control of all human
infectious diseases relies on a combination of
prevention wherever possible (including actions to
reduce or block transmission between people) and
rapid suppression of outbreaks where they do
occur, alongside the use of effective treatment
options, where available. To do this, insights into
the biology and behaviour of the pathogens that
cause disease are required, and as quickly as
possible; DNA/RNA sequencing is an important
tool for obtaining this information. Genomic
epidemiology — powered by sequencing —
is an essential element in the design of effective
prevention and control measures.

6 OXFORD NANOPORE TECHNOLOGIES | SEQUENCING, GENOMIC EPIDEMIOLOGY, AND INFECTIOUS DISEASE

Types of pathogen and exemplar diseases

Viral diseases
Declared a global pandemic in March 2020, COVID-19, the
respiratory disease caused by SARS-CoV-2, has claimed
the lives of over 2 million people to date (February 2021).

Bacterial diseases
Responsible for over 10,000 deaths and health care costs
of $2 bn per year in the US alone, methicillin-resistant
Staphylococcus aureus (MRSA) is resistant to many
first-line antibiotics.

Fungal diseases
First described in 2009 and commonly acquired in
hospitals, Candida auris is associated with high mortality
rate if detected late. Some strains are resistant to all three
available classes of antifungals.

Parasitic diseases
Transmitted by infected mosquitoes, Plasmodium
falciparum is the predominant cause of malaria,
which results in over 400,000 deaths per year.

7
What is genomic epidemiology?
KEY MESSAGES
• Genomic epidemiology provides the detailed
insights required to prevent and manage
infectious disease outbreaks
• Easily deployable genome sequencing
technologies are integral to this approach,
delivering rapid results in centralised
or near-sample environments
“
8 OXFORD NANOPORE TECHNOLOGIES | SEQUENCING, GENOMIC EPIDEMIOLOGY, AND INFECTIOUS DISEASE
Epidemiology is the study of who develops disease,
and why. Understanding how diseases occur and
spread in different groups of people, including which
people are at greater risk, helps plan strategies to
prevent and manage them.
Genomics is the study of the genome — the full set
of genetic information, providing coded instructions
for living things to grow, function, and reproduce.
Modern technologies make it possible to read
(sequence) and understand (analyse) genomes.
Genome sequencing has already revealed a great
deal about how genomes are involved in health and
disease, and more is being discovered all the time.
All countries must develop a system
for immediately sharing genome
sequences of any new pathogen...
Global Preparedness Monitoring Board3
The rapid development of genome sequencing
technologies has enabled the use genomic
epidemiology for infectious disease control —
combining genomic data from pathogens with
epidemiological investigation to understand how,
where, and why an infectious disease emerges and
spreads. This can inform decisions to deploy a
variety of responsive control measures, for example
quarantining cases and contacts, drug treatment
strategies, enhanced hospital infection control
procedures, strategic deployment of mosquito nets
to relevant areas, curbs on travel or social contact,
and so on.
“
Figure 2: In-field surveillance of Zika virus
The advent of highly portable sequencing devices
has enabled low-cost disease surveillance and
characterisation at point of infection, providing
faster access to informative results. Device
shown: MinION™ Mk1B from Oxford Nanopore
Technologies. Image courtesy of Professor Nuno
Faria, University of Oxford, UK.

9
How genomic epidemiology improves disease control
KEY MESSAGES
• Genome sequencing enables pathogen
identification, characterisation, and monitoring
“
— vital for design of precise diagnostic tools
and therapeutics
• Identification of pathogen source and
transmission routes supports effective
outbreak management
• Routine analysis of confirmed clinical cases
allows identification of novel pathogen variants
and tracking of associated pathogenic traits
(e.g. transmissibility and virulence)
• Pathogen surveillance is key to early detection
and successful disease control
Traditional epidemiological techniques
such as the generation of good clinical,
environmental, and geographical data
are vital for effective infectious disease
management. The additional inclusion of
genomic analysis provides a greater level
of precision, resolving potential ambiguities
in the data and supporting further actionable
insights for disease control (Figure 3).
10 OXFORD NANOPORE TECHNOLOGIES | SEQUENCING, GENOMIC EPIDEMIOLOGY, AND INFECTIOUS DISEASE
Pathogen identification
Genome sequencing provides a highly accurate
means of precisely identifying and characterising
the organism(s) causing infectious disease, which
is especially important in outbreak situations, and
most of all for new pathogens.
[Whole-genome sequencing]
will improve the accuracy
and effectiveness of disease
surveillance, outbreak
investigation and evaluation
of prevention policies by
enhanced assessment of
disease and drug resistance
transmission dynamics.
“ genome of the pathogen of interest. Such targeted
European Centres for Disease Control10
For example, scientists examining the sudden
outbreak of pneumonia in Wuhan, China, in late
2019 applied technique known as metagenomic
sequencing — where nucleic acids from all
organisms in a sample are analysed — to quickly
identify the microbe behind the disease as a new
coronavirus, SARS-CoV-211.
The technique of metagenomic sequencing,
which requires no prior knowledge of the infectious
organism, also allows the identification of
co-infections, where multiple different pathogens
may be present in a single sample. For example,
deploying real-time metagenomic sequencing to
COVID-19 patients in intensive care units has been
shown to enable the identification of secondary
infections, antimicrobial resistance, and hospital-
associated transmission12.
Once the pathogen responsible for a disease has
been identified, it is possible to design sequencing
assays that specifically detect and amplify only the
assays often support faster time to results, lower
sequencing and analysis costs, and can be utilised
for samples with lower levels of pathogen.
Understanding transmission
Rapidly replicating pathogens tend to accumulate
mutations in their genetic code. By comparing
pathogen genomes obtained through genome
sequencing (phylogenetic analysis), these genetic
differences can be used to identify how closely
related each pathogen is to another (Figure 4).
Combined with traditional epidemiological data
(e.g. time, location, exposure), this enables rapid
and highly accurate tracking of the sources and
transmission routes of the disease.
 • Surveillance for • Accurate diagnosis • Comparison with
known pathogens • Distinguish from other pathogens
• Introductions of other pathogens • Insights about disease
new pathogens • Determine extent • Inform design of diagnostics,
of infections therapeutics, and vaccines

• Timely, precise • Implications of changes • Sources and reservoirs

decision-making for in pathogens of infection
outbreak control • Progression and pattern • Sources and patterns
• Nature, target, and of infections of transmission
extent of interventions • Impact of interventions

Figure 3:
How genomic data informs infectious disease control.

11
Figure 4: Phylogenetic trees show the evolutionary relationship Identifying outbreak origin
between organisms or strains of the same organism By comparing the genome sequence of the novel
Hypothetical phylogeny showing inferred relationship of viruses
coronavirus, now called SARS-CoV-2, the cause of
isolated from different host organisms. The longer the horizontal
line, the larger the amount of genetic change. Figure adapted the COVID-19 disease, against databases of other
from ARTIC Network13. pathogen genomes, the virus was shown to be
related to the SARS-CoV-1 virus that originally
Camel virus emerged in Guangdong, China, and caused the
2003 SARS outbreak. The genome sequence of
subsequently termed SARS-CoV-2 virus also
revealed a high degree of similarity to certain bat
Camel virus coronaviruses, suggesting a potential origin for
the new disease. By identifying outbreak origin,
Human virus containment measures can be put in place to
prevent further spread.

Patterns of transmission
Human virus Routinely comparing the genetic code of pathogens
from infectious disease samples during clinical
outbreaks can provide significant insights into
Bat virus
sources of infection and routes of transmission.
Bat virus Thanks to new ultra-rapid sequencing technology,
these analyses are now possible in near real-time
(as opposed to retrospectively over weeks and
months) and at scale, and can thereby actively
Bat virus inform ongoing outbreak management (Figure 5).

Bat virus
Whale virus

Whale virus

12 OXFORD NANOPORE TECHNOLOGIES | SEQUENCING, GENOMIC EPIDEMIOLOGY, AND INFECTIOUS DISEASE

Figure 5: Monitoring pathogen
evolution and tracking transmission
All organisms gain mutations in their
genetic code over time. By sequencing
and comparing the genetic code of
pathogen samples it is possible to
determine how closely they are related
to each other, thereby supporting the
identification of transmission routes,
which can inform public health response.

Key:

Mutation

Viral genome sequenced

13
 These advances allow infectious disease experts to monitor the
outbreak and determine whether different strains of the pathogen
are emerging over time, what their implications may be for the likely
progression of the outbreak, and what changes in prevention or
treatment measures may be needed. For example, during the
COVID-19 pandemic, genomic epidemiology has been used to
differentiate international introductions from domestic spread of the
virus, and provide evidence to support a range of public health
interventions — from limiting international travel and implementing
robust healthcare infection control procedures (see Case study 1)
to closing shops, restaurants, and schools, on both a national and
regional level (see page 18).
Genomic surveillance can also uncover ‘cryptic’ or hidden
transmission pathways in instances where traditional epidemiological
observations may not be suggestive of an outbreak. This is
particularly useful for diseases with mild or non-specific clinical
symptoms. For example, genomic epidemiological analysis of Zika
virus samples during the 2015–16 outbreak in North and South
America not only traced its origin to Brazil, it also revealed that the
virus was circulating there for at least a year before the first reported
cases14. Had routine genomic epidemiological surveillance been in
place, the outbreak could have been detected much sooner and steps
taken to prevent spread to other countries, thereby vastly reducing
the devastating number of affected births.
“
Member States should urgently increase
[SARS-CoV-2] genome sequencing to at
least 5% and preferably 10% of positive
test results … to identify the progression
of the variants or detect any new ones.
“ pathogen, the faster appropriate steps to manage
European Commission16
14 OXFORD NANOPORE TECHNOLOGIES | SEQUENCING, GENOMIC EPIDEMIOLOGY, AND INFECTIOUS DISEASE
Pathogen characterisation
In addition to enabling precise pathogen
identification, genome sequencing data can be used
to infer significant information about the biology of
the pathogen. This can be achieved through existing
knowledge on organisms with similar genetic
composition and through lab experiments where
different genomic variants — either naturally
occurring or experimentally introduced are linked
to the ability of the organism to cause disease.
Understanding the genetic code of a given
pathogen allows researchers to develop molecular
assays that provide a rapid, accurate, and cost-
effective means of diagnosing the pathogen in
clinical samples. Such assays can be applied at
a scale and speed far above that of whole-genome
sequencing; however, for optimal outbreak
response, once identified, positive samples should
still undergo whole-genome analysis. Design and
research for novel vaccines and therapeutics is
also supported through whole-genome analysis,
and again speed may be critical — for example,
in developing novel vaccines such as those for
SARS-CoV-2, or in modifying existing vaccines
to be effective against dominant new strains
of a pathogen (see Case study 4).
Outbreak monitoring
Monitoring genomic evolution of a pathogen during
an outbreak is of vital importance. Novel variants
can alter the ability of a pathogen to cause disease,
as has been evidenced by the increased
transmissibility of the SARS-CoV-2 variants B.1.17,
B.1.351, and P1, first detected in the UK, South
Africa, and Brazil respectively. They may also
reduce the effectiveness of diagnostic assays,
compromising disease control initiatives. Critically,
they may reduce the efficacy of disease therapeutics
such as vaccines, so called vaccine escape.
Outbreak surveillance
New outbreaks caused by previously unknown
or substantially changed pathogens can cause
considerably more ill health and social and
economic damage, due to a lack of immunity in
human populations. For example, the constant
gradual genetic changes in influenza viruses
(combined with seasonal weather) drive regular
epidemics, but occasional big shifts (such as when
an animal influenza virus gains the ability to infect
humans) can cause pandemics. A pathogen that
is easily passed between people and to which they
have little or no natural resistance has potentially
devastating capacity to spread around the world.
The faster information can be learnt about the
the outbreak can be taken. This is why effective
surveillance to monitor potential new disease
threats is so important.
“ That Zika was circulating silently
across most of the Americas
highlights the need for a better
surveillance system for Zika
virus across the globe. There is “
also a need to extend genomic
surveillance to other pathogens.
Professor Nuno Rodrigues Faria, University of Oxford

15
Precise, adaptable, rapid management of a novel virus with genomic epidemiology
(COVID-19 example)

SCENARIO A SCENARIO A

? ?

DETECTION ?

OF NEW CASES SEQUENCING ANALYSIS

New COVID-19 cases SCENARIO B A sample is taken Each viral genome SCENARIO B
are confirmed via from every new case is analysed
clinical diagnostic test, and the SARS-CoV-2 alongside publicly
revealing new clusters. viral RNA extracted. available genome
?
sequences, to
?
The whole viral determine which
? genome is sequenced other cases they
?
for each sample. are most closely
related to.
Where were these Identification of small
individuals infected? differences in the viral
genomes, combined with
Do these represent a data from individuals on
single cluster or many? their movements, reveals
How many more people potential sources
are at risk of infection? of transmission.

How can further cases be

prevented effectively?

16 OXFORD NANOPORE TECHNOLOGIES | SEQUENCING, GENOMIC EPIDEMIOLOGY, AND INFECTIOUS DISEASE


TARGETED ACTION
Clusters of transmission and
individuals who may have been
exposed and identified.
With this information, precise
public health measures can now
be implemented to limit further
spread — without disruption to
unaffected areas.
SUPPORTING PUBLIC
SCENARIO A HEALTH EFFORTS
In the event that a new variant or
Cases are revealed strain is identified, this information
to belong to the same
cluster, originating is rapidly fed back into testing and
from one location. vaccine development.
SCENARIO B Genomic epidemiology
Cases are revealed
allows assessment of further
to result from multiple, risk of transmission and
separate transmission suitable prevention action.
events, with the
potential for more
ACCELERATING
widespread exposure. COVID-19 RESEARCH
The new data is shared across
the scientific community, enabling
further outbreak tracking and
providing crucial information
for research.
17
Implementing genome sequencing for outbreak control
KEY MESSAGES
• Global sharing of genomic epidemiology
data is vital for disease management
• Centralised laboratory facilities for genome
sequencing offer large-scale, high-
throughput capacity
• Localised, near-sample deployment of
genome sequencing offers additional
capacity for rapid and responsive analysis
at point of need
• Low-cost, portable sequencing technology
enables genomic epidemiology in remote
and resource-limited locations
18 OXFORD NANOPORE TECHNOLOGIES | SEQUENCING, GENOMIC EPIDEMIOLOGY, AND INFECTIOUS DISEASE
As we have seen, genomic epidemiology offers
a critical tool to support rapid and effective
assessment of infectious disease threats and
targeted, cost-effective control of outbreaks.
This is a vital capability for local and national
governments and health systems around the world.
The ability to share genomic epidemiological and
related data nationally and internationally is highly
valuable, to enable the design and roll-out of
rapid and effective at-scale testing and inform
interventions against local, epidemic, and
pandemic outbreaks.
To achieve this, a balance between centralised
and localised sequencing capacity may be needed.
Central coordination of regional or national
responses is obviously desirable and may include
larger laboratories with trained staff able to routinely
receive and process large numbers of samples,
and to analyse, store, and share large-scale data.
However, the availability of such facilities will
naturally vary between regions and countries, and
for a range of practical reasons, such as sample
transport logistics, availability of skilled staff, capital
investment resources, and lines of communication
with public health outposts.
Distributed sequencing centres that operate at or
near the site of sample collection are an important
addition to genomic surveillance systems; they can
significantly increase the speed with which results
can be returned to inform local or remote data
analysis and genomic epidemiological surveillance,
thus enabling swifter and more precisely targeted
local interventions to control outbreaks. In more
remote locations, it is also possible to use very small
mobile sequencing units, such as the ‘suitcase
laboratory’ used to support the 2015 West African
Ebola18 and 2016 South American Zika outbreaks19,
and rabies elimination initiatives 20,21.
Establishing and maintaining local capacity for rapid
deployment of pathogen genomic sequencing can
provide a critical time advantage in containing
outbreaks. The recent development of low-cost,
portable sequencing technology along with
streamlined, real-time systems for data
interpretation now makes this feasible.
“ Building a strong and resilient global
sequencing network can maximize
the public health impact of sequencing,
not only for SARS-CoV-2 but also
“
for future emerging pathogens.
World Health Organization
Genomic sequencing of SARS-CoV-2: a guide to implementation for maximum
impact on public health17

19
 “ Studying the virus’s
genome helps to highlight
cryptic or hidden
transmission. That’s the
real power of it — you can “
detect outbreaks and act
while they’re happening.
Dr. Estee Török, University of Cambridge /
Addenbrookes Hospital24

20 OXFORD NANOPORE TECHNOLOGIES | SEQUENCING, GENOMIC EPIDEMIOLOGY, AND INFECTIOUS DISEASE Credit: Anastasia Taylor Lind
CASE STUDY
Local control of COVID-19 community and hospital outbreaks
UK, 2020
As a new pandemic took hold across the
UK, hospital admissions of patients with
COVID-19 surged, including at the
Cambridge University Hospital. It was
very important to understand where and
how these infections were spreading.
The recently established COVID-19
Genomics Consortium UK22 swung
into action; a world-leading distributed
network of hospitals, public health
agencies, and academic partners,
with a mission to provide rapid, high-
throughput whole-genome sequencing
of SARS-CoV-2 samples.
The local Public Health England clinical We’re able to combine genomic
microbiology laboratory and the University of
Cambridge Department of Pathology worked
data with patients’ medical
records to provide real time
together to sequence pathogen genomes from
healthcare-associated COVID-19 infections within information to help the hospital
24 hours of receiving samples from patients. They
review its infection control on a
analysed combined genomic and epidemiological
weekly basis. It’s also highlighted
data, revealing a level of detail not detectable from
the epidemiological data alone. In six weeks, they
found over thirty different clusters of related cases
from 1,000 viral genomes — including small
outbreaks that would otherwise have been hidden
possible transmission networks
less well documented, such as
care homes, outpatient units
and ambulance services.
“
amid the bigger picture of infections. This made
it possible to identify distinct outbreaks linked
Professor Ian Goodfellow, University of Cambridge25
to specific locations in hospital and community
settings, information that was immediately fed back
Examination of the viral genome sequences helped
to doctors, managers, and infection control experts,
to reveal outbreaks and sources that would
allowing them to act quickly to prevent further
otherwise have been lost to view.
infections from the sources identified23.
The genomic data also supported wider efforts,
For example, results revealed a cluster of COVID-19
feeding into a central database and enabling a
patients in different parts of the hospital with
national genomic epidemiology overview of the
near-identical sub-types of the SARS-CoV-2 virus,
spread of SARS-CoV-2 across the UK — for
strongly suggestive of a shared origin for these
example, determining that there had been over
cases. It was found that these patients all had
1,300 separate early introductions of the virus to the
kidney disease and had visited the hospital
country, mostly from other countries in Europe such
outpatient dialysis clinic on the same day, most
as Spain and Italy, rather than from China where the
travelling in the same patient transport vehicle.
pandemic began.
Closing the dialysis clinic was not an option, so
instead both clinic and vehicle were intensively
cleaned, and new personal protective equipment
and social distancing measures swiftly put in place.
There were no further cases amongst the
dialysis patients.
21
 “ Real-time sequencing of
viruses can reveal crucial
details that contribute to
the understanding and the
control of infectious
disease outbreaks. It is
now possible to resolve
chains of transmission to
a level of detail otherwise
unachievable using
traditional methods.
“
Nigerian Government press release27

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CASE STUDY

Tracking transmission in a Lassa fever outbreak

Nigeria, 2018 The Nigerian Centre of Disease Control made an The genomic analysis results were communicated
urgent call for genomic sequence data on Lassa immediately to the Nigerian government and to the
In 2018, a 10-fold rise in the number fever virus strains involved in the outbreak, which World Health Organization. Combined with

of Lassa fever cases in Nigeria raised was in a geographically remote setting with poor conventional epidemiological investigations, they
transport accessibility. This would normally have showed that there were no signs of a new and more
concern that the virus causing the meant that samples would need to be shipped over dangerous strain of the virus emerging. Instead,

disease had evolved to allow easier a long distance for sequencing in the national a wide variety of strains were involved, suggesting
reference laboratory, an extremely slow process. that cases were mostly caused by independent
transmission between humans — Instead, an international team of scientists used transmission events of the virus to humans from

potentially the beginning of a major a portable nanopore-based sequencing device rats, allaying fears that a major outbreak driven
to provide real-time genomic analysis of 36 viral by human-to-human transmission was imminent26.
outbreak. It was important to understand samples, followed by a further 85 samples from

as quickly as possible whether or not other cases to confirm their findings. This knowledge also meant that limited public health
resources could be focused most effectively on
this was the case. community engagement about rodent control,
environmental sanitation, and safe food storage.

23
“ A great deal [of] vigilance
and monitoring of animal
populations will be needed
to understand genetic
mutations and implications “
this could have for human
vaccines.
Professor Marion Koopmans, Department
of Viroscience, Erasmus MC, Netherlands33

Dr. Bas Oude Munnink, Erasmus MC, Netherlands, using the

24 OXFORD NANOPORE TECHNOLOGIES | SEQUENCING, GENOMIC EPIDEMIOLOGY, AND INFECTIOUS DISEASE portable MinION sequencer from Oxford Nanopore Technologies.
CASE STUDY
Evidence-based public health decision-making in the COVID-19 pandemic
The Netherlands, 2020
The World Health Organization received
notification of a new and infectious
respiratory disease in Wuhan, China at
the end of December 2019, and issued
the first outbreak report about the
‘pneumonia of unknown cause’ in
January 202028. These were
subsequently identified as COVID-19
cases arising from infection with the
novel SARS-CoV-2 virus. With the
pandemic potential of the new disease
quickly becoming clear, countries around
the world moved to plan their own control
measures against this new threat to
public health.
Drawing upon world-leading expertise in virology, The combination of real-time
exemplified by the Department of Viroscience at
Erasmus MC in Rotterdam, the Netherlands, opted
whole genome sequencing with
the data from the National Public
to use genomic epidemiology from the onset —
Health response team has
introducing rapid sequencing and analysis of all
patients with suspected diseases. The first cases
were identified in late February 2020 as
introductions of the virus from Italy. Cases
increased rapidly among non-travellers, including
provided information that helped
decide on the next steps in the
decision-making.
“
healthcare workers; it was not clear how big a
Oude Munnink et al. Nature Medicine29
problem disease transmission in healthcare settings
was. This was already a sensitive political issue,
This information prompted an immediate change
given an expected shortage of personal protective
in approach to targeted public health interventions
equipment to reduce risks to health professionals.
to control the outbreaks, including the introduction
of restrictions on movement and the closure of
Rapid sequencing continued for all suspected cases
schools, catering, and sports clubs, as well as
in travellers and healthcare workers, plus local
surveillance, and by mid-March, the genomes of physical distancing measures at regional (and
subsequently national) levels30.
189 SARS-CoV-2 viruses from the Netherlands had
been sequenced — over a quarter of the sequences
available worldwide at that point. The data revealed
The Netherlands continued to use genomic
epidemiological surveillance and were able to spot
that multiple virus sub-types were circulating in the
transmission of SARS-CoV-2 variants between
population; ongoing local transmission was creating
the local and regional clusters of disease, but there
humans and minks on fur farms as early as April
2020, warning correctly that this could pose a
was little infection of healthcare workers taking
further public health risk31; in November 2020,
place in medical settings. This meant that
Danish authorities enacted a cull of all mink after
community transmission was the main mode of
a new viral variant transmissible to humans and
spread within the Netherlands at this point; there
with the potential to reduce the effectiveness
were also indications that mass gatherings such as
of new vaccines emerged32.
festivals could be acting as super-spreading events.
25
“ Had this virus caused
a severe outbreak or
pandemic, our proactive
surveillance efforts and
vaccine derivation would
have provided an
approximate 8-week time
advantage for vaccine
manufacturing.
“
Rambo-Martin and Keller et al. mSphere34

26 OXFORD NANOPORE TECHNOLOGIES | SEQUENCING, GENOMIC EPIDEMIOLOGY, AND INFECTIOUS DISEASE

CASE STUDY
Speeding up delivery of an effective vaccine for a new swine flu
USA, 2018
Influenza A viruses infect a wide range
of animals, and can sometimes move from
these animal hosts to infect humans, with
potentially serious effects; the 2009 H1N1
flu pandemic arose from a swine-human
virus transmission event. Since then, there
have been hundreds of known human
cases of swine-origin influenza in the
United States, most commonly from
exposure at agricultural fairs.
Part of routine work to limit the risks of a future flu
pandemic is genomic surveillance of circulating
viruses in swine and other animals. Genomic data
can be used to develop new candidate vaccine
viruses to form the basis for a new vaccine before
an outbreak occurs in humans; however, collecting
data typically takes weeks or even months —
precious response time lost, should an unexpected
new strain with pandemic potential emerge.
In 2018, a mobile genome sequencing station was
set up at a large US swine exhibition. Scientists
analysed samples from animals that had tested
positive for influenza A virus (and neighbouring pigs)
with a commercially available rapid testing kit. Using
the rapid, portable genome sequencing platform
and an automated, real-time data analysis pipeline
— requiring neither a laboratory facility nor an
internet connection — they were able to assess the
viral genome sequences and immediately compare
them with known swine flu viruses, including current
candidate vaccine viruses.
Three different swine influenza A viruses were
identified. The most common, an H1N2 viral
subtype, was found to be genetically distinct to the
most similar World Health Organization candidate
vaccine virus — including differences in parts of the
genome known to determine vaccine efficacy. That
meant that if this virus subtype did start to infect
humans, there was no rapid path to producing
an effective vaccine against it.
As an exercise in pandemic preparedness, all
genomic sequence data were sent to the US
Centers for Disease Control and Prevention (CDC),
who used it to develop a synthetic candidate
vaccine virus. Importantly, the actionable genomic
analysis results were obtained within 18 hours of
setting up the mobile testing facility34. This
unprecedented speed could offer a critical time
advantage in mobilising design and production
of a new vaccine to protect against a new influenza
virus threat.
27
 “ This study underscores the
need for greater genomic
surveillance of the SARS-
CoV-2 virus, especially at
the regional level where
novel variants will first
emerge. Modern genomic
surveillance enables
observation of evolution in
near real-time, prediction
of major shifts in viral “
fitness, and assurance that
vaccines are kept current.
Pater et al. bioRxiv42

28 OXFORD NANOPORE TECHNOLOGIES | SEQUENCING, GENOMIC EPIDEMIOLOGY, AND INFECTIOUS DISEASE

CASE STUDY

Identification of variants of concern

UK, 2020-21 This infrastructure enabled COG-UK to monitor B1.351 and P1, first identified in South Africa40 and
different mutations emerging in the viral genome Brazil/Japan41 respectively – also associated with
The recent identification of a number of as the virus circulated in the population, including increased transmissibility. Further variants are also

SARS-CoV-2 variants of concern (VOC) a new lineage of SARS-CoV-2 called B.1.1.7 being identified in the United States42.
(VOC202012/01), often referred to as the ‘UK
has demonstrated the importance of variant’37. B.1.1.7 has a number of changes, The identification of these variants led to

ongoing genomic surveillance to monitor particularly in the Spike protein, and increased in widespread global public health action, including
frequency in late 2020, even with lockdown renewed national lockdowns and a decrease in or
changes in the viral genome sequence and measures in place, compared to other variants. total ban on travel between specific areas or

their impact on virus biology. In the UK, the These data showed that the genetic changes in countries. It also precipitated intensive study of
B.1.1.7 had made the virus more transmissible38. these variants in the laboratory, to better understand
world-leading genomic surveillance Changes to the Spike protein are of particular any potential impact on the effectiveness of

infrastructure established by the COG-UK interest and concern because it is this protein that vaccines and diagnostics developed from genome
enables the virus to enter human cells; it is also the sequences produced early in the pandemic.
consortium, funded by the UK government target for many current vaccines and diagnostics39.

and the Wellcome Trust, had sequenced

The identification of B.1.1.7 alerted the global
over 200,000 SARS-CoV-2 genomes by community to the emergence of a more

late January 2021, around half of the global transmissible variant. Subsequent international
sequencing efforts identified other lineages —
total at that point 35,36.

29
Future-proofing for infectious disease control
Making the most of globally competitive In many countries, this distributed, real-time
genomic analysis approach is already enabling
technologies for genomic sequencing is management of the current COVID-19 pandemic,

the key to global, national, and local and it will undoubtedly also ensure more timely
intervention and positive outcomes for future
preparedness to deal with new and outbreaks of all kinds.

evolving disease threats. Investing in these

Learn more about the application of portable,
genomic tools — including those that can real-time sequencing to the genomic epidemiology

be deployed quickly and flexibly where of COVID-19 at www.nanoporetech.com/covid-19.

need arises and without major

infrastructure or training requirements —
is an essential defence against the very
considerable health, economic, and social
risks of infectious disease outbreaks.

30 OXFORD NANOPORE TECHNOLOGIES | SEQUENCING, GENOMIC EPIDEMIOLOGY, AND INFECTIOUS DISEASE

“ The accelerated integration of
genome sequencing into the
practices of the global health
community is a must if we
want to be better prepared
“
for the future threats.
Sylvie Briand, Director World Health
Emergencies Programme, World
Health Organization17

31
About Oxford Nanopore Technologies
Oxford Nanopore has developed
ground-breaking genome sequencing
technology that has been utilised
extensively across the world to deliver
fast and comprehensive insights into
infectious disease outbreaks, including
COVID-19, Ebola, Zika, and many more.
32 OXFORD NANOPORE TECHNOLOGIES | SEQUENCING, GENOMIC EPIDEMIOLOGY, AND INFECTIOUS DISEASE
Benefits of nanopore sequencing technology include:
• Real-time data streaming — faster access
to actionable results
• Portable pocket-sized devices — ideal for
decentralised, near-sample analyses
• High-throughput benchtop platforms —
enabling high-volume sample testing
• Streamlined, automatable sample preparation
— reliable results with minimal hands-on time
• Low cost — starting at just $1,000 and
capital-free purchase plans
In addition to informing genomic epidemiology,
nanopore technology has been used to develop and
run precise diagnostic assays, as evidenced by the
recent LamPORE™ COVID-19 test*, which offers
low-cost, scalable access to highly accurate
diagnosis of SARS-CoV-2.
* LamPORE™ COVID-19 is CE marked for in vitro
diagnostic use. Please check with your local sales
representative for availability in specific markets.
Figure 6:
A range of nanopore sequencing devices are
available — from portable Flongle™ and MinION
devices, to compact, high-throughput,
GridION™ and PromethION™ devices.
VolTRAX™ offers streamlined and portable
automated sample preparation.
Sequencing for COVID-19 Related resources
(Clickable links)
Throughout the COVID-19 pandemic, researchers
in the public health and scientific community have
Video: How nanopore
demonstrated the utility of rapid, nanopore sequencing
sequencing works
to enable quick responses to evolving challenges.
Nanopore sequencing delivers:
Getting started guide:
metagenomic sequencing
• Full virus genome sequencing in <8 hours

• Scalable analysis of 1–480 samples on a single device White papers: Clinical

research; TB; Microbiology
• Detailed protocols and comprehensive support

• Data analysis tools and resources Nanopore sequencing

for COVID-19
How are scientists using
nanopore sequencing to
research COVID-19?

Samples
are collected

Validated SARS-CoV-2
RT-PCR test performed

SARS-CoV-2 SARS-CoV-2
negative samples: positive samples
used as negative controls

Targeted SARS-CoV-2
nanopore sequencing

COVID-19 infographics
How?
Targeted amplification of SARS-CoV-2
genome + multiplexed, rapid nanopore
sequencing

What are the results?

From RNA to full SARS-CoV-2
consensus sequence in ~7 hours

How can this be used?

Genomic epidemiology: analyse
variants & mutation rate, track
spread of virus, identify clusters
of transmission

Metagenomic
nanopore sequencing
How?
1 x RNA metagenomic sequencing run
1 x DNA metagenomic sequencing run

What are the results?

RNA: data for RNA viruses
(including SARS-CoV-2)
+ microbial transcripts
DNA: data for bacteria + DNA viruses

How can this be used?

Characterise co-infecting bacteria &
viruses, identify any correlation of risk
factors, research potential future
treatment implications

What's next?

Whole human genome sequencing: investigate

what might cause different responses to the virus
in different people based on their genome

Immune repertoire: assess response of the

Customer community
immune system to SARS-CoV-2 infection by
sequencing of full-length immune cell receptor
genes and transcripts

SARS-CoV-2 Direct RNA whole genome

sequencing: assess viral genome in its native
RNA form and the effect of base modifications

Find out more at

nanoporetech.com/covid19

COVID-19 timeline
Oxford Nanopore Technologies, the Wheel icon, GridION, PromethION and MinION are registered trademarks of Oxford Nanopore Technologies in various countries.
© 2020 Oxford Nanopore Technologies. All rights reserved. Oxford Nanopore Technologies' products are currently for research use only. IG_1061(EN)_V1_03April2020

LamPORE COVID-19
assay*

Discover more at www.nanoporetech.com/covid-19 Visit www.nanoporetech.com

33
Figure 7:
The versatile GridION device from Oxford Nanopore
provides highly scalable, real-time sequencing capability.

34 OXFORD NANOPORE TECHNOLOGIES | SEQUENCING, GENOMIC EPIDEMIOLOGY, AND INFECTIOUS DISEASE

Glossary
epidemic: widespread occurrence of an infectious disease
in a regional or national community at a specific time above
normal or expected levels
epidemiology: study of how often diseases occur in different
groups of people and why, typically examining the distribution
of disease in specific populations and the associated causes
or risk factors
DNA: deoxyribonucleic acid, the hereditary material in
humans and almost all other organisms that contains genetic
information and passes it between generations. DNA contains
the instructions needed for an organism to develop, survive,
and reproduce
DNA / RNA sequencing: process to determine the precise
sequence (order) of the four chemical ‘bases’ that make up
the DNA or RNA molecule, in order to understand what it does
genome: complete set of all the genetic material of an
organism, usually DNA (some viruses have RNA genomes)
genomics: study of the genome
genomic epidemiology: study of how variations in genomes
of pathogens or their hosts influence health and disease,
including how common specific variations are, how they
interact with environmental factors, and how they contribute
to disease risk
genome sequencing: determining the genetic sequence of the
complete genome
lineage: sequence of species each of which is considered to
have evolved from its predecessor; in the case of viruses, may
refer to subtly different versions of a given viral species that
have evolved over time from an ancestor virus
microbe: microscopic organism, for example viruses
and bacteria
mutation: alteration in the genome of an organism; change
in DNA sequence
outbreak: sudden occurrence of disease cases in excess
of normal or expected levels, usually (but not necessarily)
caused by an infectious agent
pandemic: epidemic occurring worldwide, or over a very wide
area, crossing international boundaries and usually affecting
a large number of people; usually taken to exclude expected
seasonal epidemics
pathogen: microbe or microorganism that can cause disease
phylogenetic analysis: examination of the evolutionary
development of an organism or a particular characteristic
of an organism
RNA: ribonucleic acid, a molecule that transfers information
from the genome into proteins. Some viruses (including
coronaviruses) use RNA, as opposed to DNA, as their
genetic material
real-time sequencing: scientific technique that reads and
reports DNA or RNA sequences simultaneously, as opposed
to older methods that first capture and then report the
sequence information in bulk after the sequencing run
vaccine escape: when the circulating strain of an infectious
disease mutates (changes) such that the protective immune
response elicited by vaccination is ineffective and does not
prevent infection and disease; see also viral escape
variant: specific region of the genome that differs between
two genomes; sometimes used to refer to a common point
of variation where mutation is used to refer to a rare change;
sometimes used to refer to a different viral strain with
a changed genome
variant of concern (VOC): a pathogen strain with a genomic
change or changes that may increase its ability to infect
people, to be transmitted between people, or to cause
more serious disease in people. Variants that are more
easily spread between people in an infectious disease
outbreak have an advantage over less easily spread
versions of the pathogen
viral escape: when the circulating strain of an infectious
disease mutates (changes) such that existing, protective
immune responses become ineffective and do not prevent
disease; see also vaccine escape
strain: genetic variant or subtype within a species, particularly
important in microbes that reproduce and develop genetic
changes very rapidly; a new strain is usually considered to
have emerged if the microbe has genetic variants that affect
how easily it can infect people, spread between people,
or cause more or less serious disease in infected people
35
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37
Oxford Nanopore Technologies
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Oxford Nanopore Technologies, the Wheel icon, Flongle, GridION, LamPORE, MinION, PromethION, and VolTRAX are registered
trademarks of Oxford Nanopore Technologies Limited in various countries. All other brands and names contained are the property of
their respective owners. © 2021 Oxford Nanopore Technologies Limited. All rights reserved. Oxford Nanopore Technologies products
are not intended for use for health assessment or to diagnose, treat, mitigate, cure, or prevent any disease or condition.

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38 OXFORD NANOPORE TECHNOLOGIES | SEQUENCING, GENOMIC EPIDEMIOLOGY, AND INFECTIOUS DISEASE